Trypanosoma cruzi trypanothione reductase inhibitors: phenothiazines and related compounds modify experimental Chagas' disease evolution.
Trypanosoma cruzi trypanothione reductase inhibitors: phenothiazines and related compounds modify experimental Chagas' disease evolution.
复制标题
克氏锥虫锥硫酮还原酶抑制剂：吩噻嗪和相关化合物改变实验性恰加斯病的进化。
DOI：
10.2174/1568006023337745
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Bentham Science Publisher P.A. Paglini
中科院分区：
文献类型：
--
作者：
Bentham Science Publisher H.W. Rivarola;Bentham Science Publisher P.A. Paglini
南美锥虫病影响约1800万人，拉丁美洲25%的人口有感染南美锥虫病的风险。南美锥虫病的化疗仍是一个开放的领域，是一个尚未解决的问题。硝呋替莫和苄硝哒唑目前被用于治疗这种疾病，然而，这两种药物都具有高毒性和致突变性，导致患者经常无法遵循治疗。T. Cruzi酶如锥虫硫酮还原酶代表了潜在的药物靶点，因为它们在该生物体的生命中起重要作用。对该酶进行了分离、纯化和X射线晶体学研究。吩噻嗪和相关化合物抑制锥虫硫酮还原酶，特别适合的是具有2-氯和2-三氟甲基的2-取代的吩噻嗪，其具有远程疏水补丁。必需的吩噻嗪核在其结合位点可以采用一个以上的抑制取向。吩噻嗪及其相关化合物是用于精神病治疗的药物。这些抗抑郁药通过过氧化物酶/H2 O2/系统抑制锥虫硫酮还原酶，并对外鞭毛体和三鞭毛体形式产生其他杀锥虫作用：氯丙咪嗪通过抗钙调蛋白作用;三氟拉嗪和硫利达嗪诱导线粒体破坏，异丙嗪引起严重的细胞膜解体。氯丙咪嗪和硫利达嗪在治疗实验性恰加斯病小鼠时也有效，显著改变了感染的自然演变;感染和治疗动物的心脏功能和存活率与未感染动物没有差异。吩噻嗪类化合物是治疗南美锥虫病的有效药物。还讨论了其他杀锥虫剂，如硝呋替莫司、苯并咪唑、别嘌呤醇、半胱氨酸蛋白酶抑制剂等。
Chagas' disease affects about 18 million people and 25% of the population of Latin America is at risk of acquiring Chagas' disease. The chemotherapy of Chagas' disease is still an open field and remains as an unsolved problem. Nifurtimox and benznidazole are currently used to treat this disease, however, both drugs have high toxicity and are mutagenic with the result that the patients frequently fail to follow treatment. T. cruzi enzimes such as trypanothione reductase, represent potential drug targets because they play an essential role in the life of this organism. This enzyme has been isolated, purified and studied by X ray crystallography. Phenothiazines and related compounds inhibit trypanothione reductase and a specially favoured fit is a phenothiazine with a 2- substitued with 2- chloro and 2- trifluoromethyl with a remote hydrophobic patch. The essential phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site. Phenothiazines and related compounds are drugs used in psychiatric treatments. These anti-depressants inhibit trypanothione reductase through the peroxidase/ H2O2/ system, and also exert other trypanocidal effects upon epimastigotes and tripomastigotes forms: clomipramine through an anticalmodulin action; trifluopherazine and thioridazine induced disruption of mitochondria and prometazine provoked serious cell membrane disorganization. Clomipramine and thioridazine were also effective in treatment of mice with experimental Chagas' disease, significantly modifying the natural evolution of the infection; cardiac function and survival of infected and treated animals were not different from non infected animals. Phenothiazines and related compounds are promising trypanocidal agents for treatment of Chagas' disease. Other trypanocidal agents as nifurtimox, benznidazol,Allopurinol, cystein protease inhibitors and others, are also discussed.